HIV-1 neutralizing antibodies induced by native-like envelope trimers

Sanders, Rogier W.; Gils, Marit J. van; Derking, Ronald; Sok, Devin; Ketas, Thomas J.; Burger, Judith A.; Ozorowski, Gabriel; Cupo, Albert; Simonich, Cassandra A.; Goo, Leslie; Arendt, Heather; Kim, Helen J.; Lee, Jeong Hyun; Pugach, Pavel; Williams, Melissa; Debnath, Gargi; Moldt, Brian; Breemen, Mariëlle J. van; Isik, Gözde; Medina-Ramírez, Max; Back, Jaap Willem; Koff, Wayne C.; Julien, Jean-Philippe; Rakasz, Eva G.; Seaman, Michael S.; Guttman, Miklós; Lee, Kelly K.; Klasse, Per Johan; LaBranche, Celia C.; Schief, William R.; Wilson, Ian A.; Overbaugh, Julie; Burton, Dennis R.; Ward, Andrew B.; Montefiori, David C.; Dean, Hansi; Moore, John P.

doi:10.1126/science.aac4223

Cited by 482 publications

(785 citation statements)

References 62 publications

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“…In our view, data from the A3R5 assay provide another comparative evaluation tool of the Ab responses elicited in vaccinated macaques. The neutralization breadth generated by these vaccines is as potent and comparable to that reported in a recent Env-based vaccine study using similar virus panels (13) and notably more potent than others (15,21,70), including the immunogenicity results of the studies using native-like trimers (58,71). Importantly, this study is unique because we show that the Env-specific vaccine-induced macaque polyclonal IgG was biased toward the same regions of Env mapped to NAb breadth in human subject plasma verified in our earlier studies.…”

Section: Discussionsupporting

confidence: 57%

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Achieving Potent Autologous Neutralizing Antibody Responses against Tier 2 HIV-1 Viruses by Strategic Selection of Envelope Immunogens

Hessell

Malherbe

Pissani

et al. 2016

The Journal of Immunology

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Advancement in immunogen selection and vaccine design that will rapidly elicit a protective Ab response is considered critical for HIV vaccine protective efficacy. Vaccine-elicited Ab responses must therefore have the capacity to prevent infection by neutralization-resistant phenotypes of transmitted/founder (T/F) viruses that establish infection in humans. Most vaccine candidates to date have been ineffective at generating Abs that neutralize T/F or early variants. In this study, we report that coimmunizing rhesus macaques with HIV-1 gp160 DNA and gp140 trimeric protein selected from native envelope gene sequences (envs) induced neutralizing Abs against Tier 2 autologous viruses expressing cognate envelope (Env). The Env immunogens were selected from envs emerging during the earliest stages of neutralization breadth developing within the first 2 years of infection in two clade B–infected human subjects. Moreover, the IgG responses in macaques emulated the targeting to specific regions of Env known to be associated with autologous and heterologous neutralizing Abs developed within the human subjects. Furthermore, we measured increasing affinity of macaque polyclonal IgG responses over the course of the immunization regimen that correlated with Tier 1 neutralization. In addition, we report firm correlations between Tier 2 autologous neutralization and Tier 1 heterologous neutralization, as well as overall TZM-bl breadth scores. Additionally, the activation of Env-specific follicular helper CD4 T cells in lymphocytes isolated from inguinal lymph nodes of vaccinated macaques correlated with Tier 2 autologous neutralization. These results demonstrate the potential for native Env derived from subjects at the time of neutralization broadening as effective HIV vaccine elements.

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Section: Discussionsupporting

confidence: 57%

“…6F). This result differs with recent findings that Tier 1 and Tier 2 titers induced in rabbits immunized with native-like trimers were not correlative (58).…”

Section: Neutralization Breadth Is Induced Against Heterologous Tiercontrasting

confidence: 56%

Achieving Potent Autologous Neutralizing Antibody Responses against Tier 2 HIV-1 Viruses by Strategic Selection of Envelope Immunogens

Hessell

Malherbe

Pissani

et al. 2016

The Journal of Immunology

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“…Until recently, very few immunization studies had induced even Tier‐2 autologous neutralization, let alone a broad response 90, 91, 92, 93. Post‐immune neutralization titers are lower than those seen in elite neutralizer bnAb donors, thus neutralizing Abs may be less frequent among the post‐immunization B‐cell population.…”

Section: Resultsmentioning

confidence: 99%

Identification and specificity of broadly neutralizing antibodies against HIV

McCoy

Burton

2017

Immunological Reviews

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SummaryBeginning in 2009, studies of the humoral responses of HIV‐positive individuals have led to the identification of scores, if not hundreds, of antibodies that are both broadly reactive and potently neutralizing. This development has provided renewed impetus toward an HIV vaccine and led directly to the development of novel immunogens. Advances in identification of donors with the most potent and broad anti‐HIV serum neutralizing responses were crucial in this effort. Equally, development of methods for the rapid generation of human antibodies from these donors was pivotal. Primarily these methods comprise single B‐cell culture coupled to high‐throughput neutralization screening and flow cytometry‐based sorting of single B cells using HIV envelope protein baits. In this review, the advantages and disadvantages of these methodologies are discussed in the context of the specificities targeted by individual antibodies and the need for further improvements to evaluate HIV vaccine candidates.

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“…We next examined the relationship between plasma CXCL13 and GC activity after protein immunization in animal vaccination models (6,(29)(30)(31). We first immunized mice with 4-hydroxy-3-nitrophenyl acetyl haptenated ovalbumin in aluminum hydroxide adjuvant (alum + NP-OVA).…”

Section: Plasma Cxcl13 Is Correlated With Lymph Node Gcs In Mice Aftermentioning

confidence: 99%

CXCL13 is a plasma biomarker of germinal center activity

Havenar-Daughton

Lindqvist

Heit

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

291

311

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Significantly higher levels of plasma CXCL13 [chemokine (C-X-C motif) ligand 13] were associated with the generation of broadly neutralizing antibodies (bnAbs) against HIV in a large longitudinal cohort of HIV-infected individuals. Germinal centers (GCs) perform the remarkable task of optimizing B-cell Ab responses. GCs are required for almost all B-cell receptor affinity maturation and will be a critical parameter to monitor if HIV bnAbs are to be induced by vaccination. However, lymphoid tissue is rarely available from immunized humans, making the monitoring of GC activity by direct assessment of GC B cells and germinal center CD4 + T follicular helper (GC Tfh) cells problematic. The CXCL13-CXCR5 [chemokine (C-X-C motif) receptor 5] chemokine axis plays a central role in organizing both B-cell follicles and GCs. Because GC Tfh cells can produce CXCL13, we explored the potential use of CXCL13 as a blood biomarker to indicate GC activity. In a series of studies, we found that plasma CXCL13 levels correlated with GC activity in draining lymph nodes of immunized mice, immunized macaques, and HIV-infected humans. Furthermore, plasma CXCL13 levels in immunized humans correlated with the magnitude of Ab responses and the frequency of ICOS + (inducible T-cell costimulator) Tfh-like cells in blood. Together, these findings support the potential use of CXCL13 as a plasma biomarker of GC activity in human vaccine trials and other clinical settings.T he germinal center (GC) reaction is a critical immunological process that occurs in draining lymph nodes after immunization (1). The GC response consists of antigen-specific B cells undergoing affinity maturation through a process of somatic hypermutation (SHM) of the B-cell receptor. SHM is necessary for producing high-affinity Ab responses after immunizations and infections. Influenza neutralizing Abs have substantial SHM. Particularly high levels of SHM, 15-30% amino acid mutation (2, 3), are present and necessary for broad Ab neutralization of diverse HIV strains (4, 5). Therefore, as candidate influenza and HIV vaccines are evaluated for the ability to induce broadly neutralizing antibodies (bnAbs), the quantitation and functional characterization of GC responses will be a key parameter for study. Serological analysis of vaccine-specific Ab titers provides important information, but those data are limited. Serological outcomes are measured at time points long after initial immunizations. Neutralizing Ab responses are commonly only measurable after multiple boosts. Those outcomes likely depend on GC activity and affinity maturation at much earlier time points. Several state of the art HIV vaccine strategies rely on long, multistage immunization protocols (6, 7). With bnAb responses as the goal, means of early analysis of the immune response will be essential to understand and improve on vaccination schemes that may end in failure or only partial success. One critical parameter to assess will be the ability of each immunization to generate GC responses.Central to the GC re...

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HIV-1 neutralizing antibodies induced by native-like envelope trimers

Cited by 482 publications

References 62 publications

Achieving Potent Autologous Neutralizing Antibody Responses against Tier 2 HIV-1 Viruses by Strategic Selection of Envelope Immunogens

Achieving Potent Autologous Neutralizing Antibody Responses against Tier 2 HIV-1 Viruses by Strategic Selection of Envelope Immunogens

Identification and specificity of broadly neutralizing antibodies against HIV

CXCL13 is a plasma biomarker of germinal center activity

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